NIACR1

Detailed Information

NIACR1 (Nicotinic Acid Receptor 1), also known as HCAR2 (Hydroxycarboxylic Acid Receptor 2), is a protein-coding gene located on chromosome 12p13.31 in humans. It belongs to the superfamily of G protein-coupled receptors (GPCRs). The gene encodes a seven-transmembrane protein of 330 amino acids, featuring the classical GPCR topology: an extracellular N-terminus involved in ligand recognition, seven transmembrane α-helical domains (TM1–TM7) forming the ligand-binding pocket, and intracellular loops and C-terminus mediating G protein coupling and signal transduction. A defining feature of NIACR1 is its dual ligand-binding capacity—it is a high-affinity receptor for nicotinic acid (vitamin B3, EC50 ≈ 100 nM) and a physiological receptor for β-hydroxybutyrate, a major ketone body. This dual recognition underlies its central role in metabolic regulation.

NIACR1 primarily signals through coupling with Gi/o-type G proteins. Upon ligand binding to the extracellular domain, conformational changes activate the Gi protein α-subunit, inhibiting adenylyl cyclase activity and reducing intracellular cAMP levels. This canonical pathway mediates various pharmacological effects of nicotinic acid: in adipose tissue, lowered cAMP reduces phosphorylation of hormone-sensitive lipase (HSL), inhibiting lipolysis and decreasing free fatty acid (FFA) release; in the immune system, reduced cAMP enhances ERK1/2 phosphorylation, triggering pro-apoptotic signaling and inducing neutrophil apoptosis. Additionally, NIACR1 can activate MAPK signaling via a β-arrestin-dependent pathway, contributing to anti-inflammatory responses. In specific cellular contexts, it may couple with Gq proteins to activate the PLCβ–PKC pathway and regulate calcium mobilization.

NIACR1 expression is highly tissue-specific. It is abundant in adipose tissue, where it regulates lipid metabolism; in immune cells, particularly neutrophils, monocytes, and macrophages, where it modulates inflammation; and also expressed in the intestine, skin, and brain, indicating diverse physiological functions. Notably, NIACR1 expression is dynamically regulated by metabolic states—fasting elevates blood ketone levels and upregulates NIACR1 expression in the liver and adipose tissue by 2–3 fold, while high-fat diets suppress its expression. This adaptive regulation highlights NIACR1 as a metabolic sensor linking nutritional status to cellular responses.

Figure 1. Cell types and tissues expressing HCAR2. (Tuteja S. et al., 2019)

Roles in Metabolism and Inflammation

NIACR1 plays a key role in coordinating lipid metabolism and energy homeostasis. As a potent agonist, pharmacological doses of nicotinic acid (1–3 g/day) significantly reduce serum FFA levels by 25–30%, thereby lowering hepatic VLDL synthesis. This leads to reductions in triglycerides by 20–50%, LDL cholesterol by 5–25%, and increases HDL cholesterol by 15–35%. This unique lipid profile makes nicotinic acid an important therapy for mixed dyslipidemia. Mechanistically, nicotinic acid binds to NIACR1 on adipocytes, activates Gi signaling to suppress lipase activity and lipolysis, and enhances lipoprotein lipase (LPL) activity to promote chylomicron clearance.

In inflammation, NIACR1 serves as a bridge between metabolic and immune pathways. β-Hydroxybutyrate activates NIACR1 in neutrophils, lowering cAMP and inducing caspase-3-dependent apoptosis, which alleviates excessive inflammation. In atherosclerosis models, NIACR1 agonists suppress NF-κB signaling in macrophages, reducing pro-inflammatory cytokines like TNF-α and IL-6 while increasing IL-10, an anti-inflammatory mediator. This anti-inflammatory effect is critical in metabolic diseases, where chronic low-grade inflammation contributes to insulin resistance. NIACR1 agonists improve insulin sensitivity in obese models, independent of lipid-lowering effects.

NIACR1's physiological role during energy stress is particularly notable. During fasting or ketogenic diets, hepatic production of β-hydroxybutyrate activates NIACR1 in adipose tissue to suppress lipolysis, conserving endogenous fuel. Simultaneously, NIACR1 activation in the hypothalamus modulates appetite and energy expenditure. This adaptive response helps maintain metabolic homeostasis under nutrient scarcity. However, in pathological obesity, chronic elevation of FFAs leads to downregulation and desensitization of NIACR1, disrupting metabolic balance and promoting a vicious cycle. Restoring NIACR1 sensitivity is therefore a potential strategy for treating metabolic syndrome.

Clinical Applications and Drug Development

Due to its lipid-modulating effects, nicotinic acid has been used clinically for over 50 years as a natural NIACR1 agonist. Large-scale clinical trials show that nicotinic acid, alone or combined with statins, significantly improves lipid profiles, particularly by elevating HDL-C. However, the major limitation of nicotinic acid therapy is the flushing side effect—about 80% of patients experience facial and neck flushing with burning and itching, reducing compliance. This effect arises from NIACR1 activation in Langerhans cells of the skin, which release prostaglandin D2 (PGD2), leading to vasodilation via the DP1 receptor. To mitigate this, sustained-release formulations and co-administration with prostaglandin inhibitors (e.g., laropiprant) have been developed, reducing flushing incidence by 50–70%.

While new lipid-lowering agents such as PCSK9 inhibitors challenge nicotinic acid's role, recent findings suggest that NIACR1 agonists may have broader therapeutic potential beyond lipid control. In non-alcoholic fatty liver disease (NAFLD) models, the selective NIACR1 agonist MK-1903 reduces hepatic fat content (−28.6%) and fibrosis markers by inhibiting de novo lipogenesis and improving insulin sensitivity. In atherosclerosis, NIACR1 agonists enhance plaque stability by reducing macrophage inflammation and promoting collagen deposition, thereby lowering rupture risk. These pleiotropic effects position NIACR1 as a promising target for managing metabolic syndrome.

Current drug development targeting NIACR1 focuses on two main classes: selective agonists that retain metabolic benefits while minimizing flushing, and biased ligands that selectively activate desirable pathways. MK-0354, a selective agonist structurally similar to nicotinic acid, exhibits improved pharmacokinetics, durable FFA suppression, and milder flushing in phase II trials. Aripidem (SCH900271), a biased ligand developed by Johnson & Johnson, preferentially activates Gi signaling without recruiting β-arrestin, completely avoiding flushing in animal models. However, some candidates like MK-0354 were discontinued during phase II due to insufficient efficacy or strategic decisions.

Table: Drug Development Landscape Targeting NIACR1

A 2024 review by Professor Jian Wu's team at Fudan University comprehensively discussed NIACR1's roles in metabolic diseases, highlighting its central position in GPCR regulatory networks. The study emphasized NIACR1's crosstalk with other metabolism-related GPCRs, such as GPR55, GPR91, and GPR119, forming a complex signaling network to maintain metabolic homeostasis. In particular, in non-alcoholic steatohepatitis (NASH), NIACR1 agonists reduce hepatic stellate cell activation and collagen deposition, alleviating fibrosis. These multi-target effects provide a solid theoretical foundation for NIACR1-based therapies.

Despite promising prospects, several challenges remain. The foremost is receptor desensitization—prolonged agonist use leads to NIACR1 internalization and degradation, diminishing responsiveness. Intermittent dosing strategies (e.g., thrice weekly) have shown promise in maintaining sensitivity in animal models. Alternatively, the development of allosteric modulators that avoid direct activation may offer a breakthrough. Moreover, tissue-specific delivery methods such as adipose-targeted nanoparticles can enhance local drug concentrations while minimizing systemic side effects. With cryo-EM resolving the 3D structure of NIACR1, structure-based drug design may enable next-generation selective modulators.

Looking forward, NIACR1 research is expanding beyond metabolism into neuroinflammation and tumor microenvironments. In Alzheimer's models, NIACR1 agonists reduce microglial inflammation and improve cognitive function. In colorectal cancer, high NIACR1 expression correlates with better prognosis, possibly by regulating tumor-associated macrophages. These findings broaden the therapeutic scope of NIACR1-targeted treatments. However, given the chronic and progressive nature of metabolic disorders, relying on a single receptor agonist is unlikely to achieve a cure. Thus, combining highly specific NIACR1 modulators with lifestyle interventions and risk factor management remains the cornerstone of effective prevention and treatment.